Bicyclic heterocycles as cannabinoid receptor modulators

ABSTRACT

The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the general Formula I: 
                         
including all pharmaceutically acceptable salts and stereoisomers, R 1 , R 2 , R 3 , R 3a , R 4 , n, Y and Z are described herein.

RELATED APPLICATION

This application claims priority benefit under Title 35 § 119(e) of U.S.Provisional Application No. 60/643,270, filed Jan. 12, 2005, thecontents of which are herein incorporated by reference.

BACKGROUND

Delta-9-tetrahydrocannabinol or Delta-9 THC, the principle activecomponent of Cannabis sativa (marijuana), is a member of a large familyof lipophilic compounds (i.e., cannabinoids) that mediate physiologicaland psychotropic effects including regulation of appetite,immunosuppression, analgesia, inflammation, emesis, anti-nocioception,sedation, and intraocular pressure. Other members of the cannabinoidfamily include the endogenous (arachidonic acid-derived) ligands,anandamide, 2-arachidonyl glycerol, and 2-arachidonyl glycerol ether.Cannabinoids work through selective binding to and activation ofG-protein coupled cannabinoid receptors. Two types of cannabinoidreceptors have been cloned including CB-1 (L. A. Matsuda, et al.,Nature, 346, 561-564 (1990)), and CB-2 (S. Munro, et al., Nature, 365,61-65 (1993)). The CB-1 receptor is highly expressed in the central andperipheral nervous systems (M. Glass, et al., Neuroscience, 77, 299-318(1997)), while the CB-2 receptor is highly expressed in immune tissue,particularly in spleen and tonsils. The CB-2 receptor is also expressedon other immune system cells, such as lymphoid cells (S. Galiegue, etal., Eur J Biochem, 232, 54-61 (1995)). Agonist activation ofcannabinoid receptors results in inhibition of cAMP accumulation,stimulation of MAP kinase activity, and closure of calcium channels.

There exists substantial evidence that cannabinoids regulate appetitivebehavior. Stimulation of CB-1 activity by anandamide or Delta-9 THCresults in increased food intake and weight gain in multiple speciesincluding humans (Williams and Kirkham, Psychopharm., 143, 315-317(1999)). Genetic knock-out of CB-1 result in mice that were hypophagicand lean relative to wild-type litter mates (DiMarzo, et al., Nature,410, 822-825 (2001)). Published studies with CB-1 small moleculeantagonists have demonstrated decreased food intake and body weight inrats (Trillou, et. al., Am. J. Physiol. Regul. Integr. Comp. Physiol.,R345-R353, (2003)). Chronic administration of the CB-1 antagonist AM-251for two weeks resulted in substantial body weight reduction anddecreased adipose tissue mass (Hildebrandt, et. al., Eur. J. Pharm, 462,125-132 (2003)). There are multiple studies that have assessed theanorexic effect of the Sanofi CB-1 antagonist, SR-141716 (Rowland, et.al., Pyschopharm., 159, 111-116 (2001); Colombo, et. al., Life Sci., 63,113-117 (1998)). There are at least two CB-1 antagonists in clinicaltrials for regulation of appetite, Sanofi's SR-141716 and Solvay'sSLV-319. Published Phase IIb data reveal that SR-141716 dose-dependentlyreduced body weight in human subjects over a 16 week trial period. CB-1antagonists have also been shown to promote cessation of smokingbehavior. Phase II clinical data on smoking cessation were presented inSeptember of 2002 at Sanofi-Synthelabo's Information meeting. This datashowed that 30.2% of patients treated with the highest dose of SR-141716stayed abstinent from cigarette smoke relative to 14.8% for placebo.

DETAILED DESCRIPTION

The present application describes compounds according to Formula I,pharmaceutical compositions comprising at least one compound accordingto Formula I and optionally one or more additional therapeutic agentsand methods of treatment using the compounds according to Formula I bothalone and in combination with one or more additional therapeutic agents.The compounds have the general Formula I

including all prodrugs, pharmaceutically acceptable salts andstereoisomers, R¹, R², R³, R^(3a), R⁴, n, Y and Z are described herein.

Definitions

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains containing 1 to 20 carbons, preferably 1 to 12carbons, and more preferably 1 to 8 carbons, in the normal chain, suchas, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl,tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl and the like. Further, alkyl groups, as definedherein, may optionally be substituted on any available carbon atom withone or more functional groups commonly attached to such chains, such as,but not limited to hydroxyl, halo, haloalkyl, mercapto or thio, cyano,alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl,carbalkoyl, carboxamido, carbonyl, alkenyl, alkynyl, nitro, amino,alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, amido, —OPO₃H, —OSO₃H, andthe like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl,2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chains of 2to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8carbons with one or more double bonds in the normal chain, such asvinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl,2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl,and the like. Further, alkenyl groups, as defined herein, may optionallybe substituted on any available carbon atom with one or more functionalgroups commonly attached to such chains, such as, but not limited tohalo, haloalkyl, alkyl, alkoxy, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxyl, heteroaryl, cycloheteroalkyl, alkanoylamino,alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or anyof the alkyl substituents set out herein.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chains of 2to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8carbons with one or more triple bonds in the normal chain, such as2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl,3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,4-decynyl, 3-undecynyl, 4-dodecynyl and the like. Further, alkynylgroups, as defined herein, may optionally be substituted on anyavailable carbon atom with one or more functional groups commonlyattached to such chains, such as, but not limited to halo, haloalkyl,alkyl, alkoxy, alkenyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl,heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or any of thealkyl substituents set out herein

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing one or more double bonds) cyclic hydrocarbongroups containing 1 to 3 rings, appended or fused, includingmonocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of3 to 20 carbons forming the rings, preferably 3 to 10 carbons, formingthe ring and which may be fused to 1 or 2 aromatic rings as describedfor aryl, which include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl,cyclohexenyl,

Further, any cycloalkyl may be optionally substituted through anyavailable carbon atoms with one or more groups selected from hydrogen,halo, haloalkyl, alkyl, alkoxy, haloalkyloxy, hydroxyl, alkenyl,alkynyl, aryl, aryloxy, heteroaryl, heteroaryloxy, arylalkyl,heteroarylalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the alkyl substituents.

The term “cycloalkylalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a cycloalkylsubstituent, wherein said “cycloalkyl” and/or “alkyl” groups mayoptionally be substituted as defined above.

Unless otherwise indicated, the term “aryl” as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl including 1-naphthyl and 2-naphthyl) and may optionally includeone to three additional rings fused to a carbocyclic ring or aheterocyclic ring, for example

Further, “aryl”, as defined herein, may optionally be substituted withone or more functional groups, such as halo, alkyl, haloalkyl, alkoxy,haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl,arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxyl, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl and/or any of the alkyl substituents set outherein.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- or 6-membered aromatic ringwhich includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen orsulfur. Such rings may be fused to an aryl, cycloalkyl, heteroaryl orheterocyclyl and include possible N-oxides as described in Katritzky, A.R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: TheStructure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984,Pergamon Press, New York, N.Y.; and Katritzky, A. R., Rees, C. W.,Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A Reviewof the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown,N.Y.; and references therein. Further, “heteroaryl”, as defined herein,may optionally be substituted with one or more substituents such as thesubstituents included above in the definition of “substituted alkyl” and“substituted aryl”. Examples of heteroaryl groups include the following:

and the like.

The term “heteroarylalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a heteroarylsubstituent, wherein said heteroaryl and/or alkyl groups may optionallybe substituted as defined above.

The term “heterocyclo”, “heterocycle”, “heterocyclyl” or “heterocyclicring”, as used herein, represents an unsubstituted or substituted stable4 to 7-membered monocyclic ring system which may be saturated orunsaturated, and which consists of carbon atoms, with one to fourheteroatoms selected from nitrogen, oxygen or sulfur, and wherein thenitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quaternized. The heterocyclic ringmay be attached at any heteroatom or carbon atom which results in thecreation of a stable structure. Examples of such heterocyclic groupsinclude, but is not limited to, piperidinyl, piperazinyl,oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl,pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl,imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, oxadiazolyl and other heterocyclesdescribed in Katritzky, A. R. and Rees, C. W., eds. ComprehensiveHeterocyclic Chemistry: The Structure, Reactions, Synthesis and Uses ofHeterocyclic Compounds 1984, Pergamon Press, New York, N.Y.; andKatritzky, A. R., Rees, C. W., Scriven, E. F., eds. ComprehensiveHeterocyclic Chemistry II: A Review of the Literature 1982-1995 1996,Elsevier Science, Inc., Tarrytown, N.Y.; and references therein.

The term “heterocycloalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a heterocyclylsubstituent, wherein said heterocyclyl and/or alkyl groups mayoptionally be substituted as defined above.

The terms “arylalkyl”, “arylalkenyl” and “arylalkynyl” as used alone oras part of another group refer to alkyl, alkenyl and alkynyl groups asdescribed above having an aryl substituent. Representative examples ofarylalkyl include, but are not limited to, benzyl, 2-phenylethyl,3-phenylpropyl, phenethyl, benzhydryl and naphthylmethyl and the like.

The term “alkoxy”, “aryloxy”, “heteroaryloxy” “arylalkyloxy”, or“heteroarylalkyloxy” as employed herein alone or as part of anothergroup includes an alkyl or aryl group as defined above linked through anoxygen atom.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine, with bromine,chlorine or fluorine being preferred.

The term “cyano,” as used herein, refers to a —CN group.

The term “methylene,” as used herein, refers to a —CH₂— group.

The term “nitro,” as used herein, refers to a —NO₂ group.

The compounds of formula I can be present as salts, which are alsowithin the scope of this invention. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred. If thecompounds of formula I have, for example, at least one basic center,they can form acid addition salts. These are formed, for example, withstrong inorganic acids, such as mineral acids, for example sulfuricacid, phosphoric acid or a hydrohalic acid, with organic carboxylicacids, such as alkanecarboxylic acids of 1 to 4 carbon atoms, forexample acetic acid, which are unsubstituted or substituted, forexample, by halogen as chloroacetic acid, such as saturated orunsaturated dicarboxylic acids, for example oxalic, malonic, succinic,maleic, fumaric, phthalic or terephthalic acid, such ashydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic,tartaric or citric acid, such as amino acids, (for example aspartic orglutamic acid or lysine or arginine), or benzoic acid, or with organicsulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acids which areunsubstituted or substituted, for example by halogen, for examplemethyl- or p-toluene-sulfonic acid. Corresponding acid addition saltscan also be formed having, if desired, an additionally present basiccenter. The compounds of formula I having at least one acid group (forexample COOH) can also form salts with bases. Suitable salts with basesare, for example, metal salts, such as alkali metal or alkaline earthmetal salts, for example sodium, potassium or magnesium salts, or saltswith ammonia or an organic amine, such as morpholine, thiomorpholine,piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for exampleethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl ordimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, forexample mono, di or triethanolamine. Corresponding internal salts mayfurthermore be formed. Salts which are unsuitable for pharmaceuticaluses but which can be employed, for example, for the isolation orpurification of free compounds of formula I or their pharmaceuticallyacceptable salts, are also included.

Preferred salts of the compounds of formula I which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate, nitrate or acetate.

Preferred salts of the compounds of formula I which contain an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines.

The term “modulator” refers to a chemical compound with capacity toeither enhance (e.g., “agonist” activity) or partially enhance (e.g.,“partial agonist” activity) or inhibit (e.g., “antagonist” activity or“inverse agonist” activity) a functional property of biological activityor process (e.g., enzyme activity or receptor binding); such enhancementor inhibition may be contingent on the occurrence of a specific event,such as activation of a signal transduction pathway, and/or may bemanifest only in particular cell types.

The term “bioactive metabolite” as employed herein refers to anyfunctional group contained in a compound of formula I with an openvalence for further substitution wherein such substitution can, uponbiotransformation, generate a compound of formula I. Examples of suchfunctional groups of bioactive metabolites include, but are not limitedto, —OH, —NH or functional groups wherein the hydrogen can be replacedwith a functional group such as —PO₃H₂ for example, which, uponbiotransformation generates an —OH or —NH functional group of a compoundof formula I.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like. Prodrugesters may also include—but are not limited to groups such as phosphateesters, phosphonate esters, phosphonamidate esters, sulfate esters,sulfonate esters, and sulfonamidate esters wherein the ester may befurther substituted with groups that confer a pharmaceutical advantagesuch as-but not limited to-favorable aqueous solubility or in vivoexposure to the bioactive component formula I.

The term “prodrug” as employed herein includes functionalization ofbioactive amine- or hydroxyl-containing compounds of formula I to formalkyl-, acyl-, sulfonyl-, phosphoryl-, or carbohydrate-substitutedderivatives. Such derivatives are formed by reacting compounds offormula I with alkylating-, acylating-, sulfonylating-, orphosphorylating reagents employing procedures known to those skilled inthe art. Alkylation of amines of formula I may result in—but are notlimited to—derivatives that include spacer units to other prodrugmoieties such as substituted alkyoxymethyl-, acyloxymethyl-,phosphoryloxymethyl-, or sulfonyloxymethyl-groups. Alkylation of aminesof formula I may result in the generation of quarternary amine saltsthat act in vivo to provide the bioactive agent (i.e., the compound offormula I).

Preferred prodrugs consist of a compound of formula I where a pendanthydroxyl is phosphorylated to generate a phosphate derivative. Such aprodrug may also include a spacer group between the compound of formulaI and the phosphate group, such as a methyleneoxy-group. Methods togenerate such a prodrug from a compound of formula I are known to thoseskilled in the art, and are listed in the references below.

Preferred prodrugs also consist of a compound of formula I where apendant amine, such as a pyridine group, is alkylated with a group, suchas methyl, to form a quarternary ammonium ion salt. Methods to generatesuch a prodrug from a compound of formula I are known to those skilledin the art, and are listed in the references below.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

Various forms of prodrugs are well known in the art. A comprehensivedescription of prodrugs and prodrug derivatives are described in:

-   -   a) The Practice of Medicinal Chemistry, Camille G. Wermuth et        al., Ch 31, (Academic Press, 1996);    -   b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);    -   c) A Textbook of Drug Design and Development, P.        Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191        (Harwood Academic Publishers, 1991);    -   d) Hydrolysis in Drug and Prodrug Metabolism, B. Testa and J. M.        Mayer, (Verlag Helvetica Chimica Acta AG, Zurich, Switzerland;        Wiley-VCH, Weinheim, Federal Republic of Germany, 2003);    -   e) Ettmayer, P.; Amidon, G. L.; Clement, B.; Testa, B. “Lessons        Learned from Marketed and Investigational Prodrugs” J. Med.        Chem. 2004, 47 (10), 2393-2404; and    -   f) Davidsen, S. K. et al. “N-(Acyloxyalkyl)pyridinium Salts as        Soluble Prodrugs of a Potent Platelet Activating Factor        Antagonist” J. Med. Chem. 1994, 37 (26), 4423-4429.        Said references are incorporated herein by reference.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration.

All stereoisomers of the compounds of the instant invention arecontemplated, either in mixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic techniques, chiral HPLC or fractional crystallization.

The compounds of formula I of the invention can be prepared as shown inthe following reaction schemes and description thereof, as well asrelevant published literature procedures that may be used by one skilledin the art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working Examples.

Abbreviations

The following abbreviations are employed in the Schemes, Examples andelsewhere herein:

-   AcOH=acetic acid-   Boc=tert-butoxycarbonyl-   Cbz=benzyloxycarbonyl-   DIPEA=N,N-diisopropylehtylamine-   DMF=N,N-dimethylformamide-   EtOAc=ethyl acetate-   Et₃N=triethylamine-   Et₂O=diethyl ether-   HPLC or LC=high performance liquid chromatography-   MeOH=methanol-   MS or Mass Spec=mass spectrometry-   NaCl=sodium chloride-   NaHCO₃=sodium bicarbonate-   Na₂SO₄=sodium sulfate-   NaOH=sodium hydroxide-   PG=protecting group-   PXPd=dichloro-bis(chloro-di-tert-butylphosphine)palladium-   RT=room temperature-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   min=minute(s)-   h=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   nM=nanomolar

Methods of Preparation

The compounds of the present invention may be prepared by methods suchas those illustrated in the following Scheme 1 to 2. Solvents,temperatures, pressures, and other reaction conditions may readily beselected by one of ordinary skill in the art. Starting materials arecommercially available or can be readily prepared by one of ordinaryskill in the art using known methods. For all of the schemes andcompounds described below, R¹, R², R³, R^(3a), R⁴, n, Y and Z are asdescribed for a compound of formula I.

Compounds of formula II are either commercially available or can bereadily prepared by one skilled in the art. Compounds of formula III canbe prepared by treating intermediate II with a brominating reagent suchas N-bromosuccinimide. The amino group of intermediate III can beprotected as an alkyl carbamate, preferably tert-butyl carbamate asshown in compounds of formula IV. Compounds of formula V can be preparedby treating bromide IV with an organolithium reagent, such asn-butyllithium at low temperature, preferably below 70° C. in an aproticpolar solvent (e.g., THF), followed by addition of a formylatingreagent, such as N-formyl piperidine or DMF. Compounds of formula VIIcan be prepared by reacting of intermediate V with a functionalizedphosphonate ester VI in the presence of a strong base (e.g., sodiumhydride) in an aprotic polar solvent (e.g., THF). Intermediate VI can bereadily prepared by one skilled in the art. Compounds of formula VIIIcan be prepared via catalytic hydrogenation under medium hydrogenpressure (e.g., 80 psi) in the presence of a platinum catalyst.Compounds of formula IX can be prepared by treating intermediate VIIIwith a strong acid (e.g., trifluoroacetic acid in dichloromethane).Compounds of formula X can be prepared by reacting intermediate IX withan alkylhalide in the presence of a base (e.g., cesium carbonate) orwith an arylhalide via a transition metal (e.g., palladium or copper)mediated reaction. Compounds of formula XI can be prepared by removingthe Cbz group in intermediate X by catalytic hydrogenolysis or a Lewisacid (e.g., iodotrimethylsilane). Compounds of formula Ia can beprepared by reacting intermediate XI with an acyl chloride or acarboxylic acid (for formation of an amide), or a chloroformate (forformation of a carbamate), or an isocyanate (for formation of a urea),or a sulfonyl chloride (for formation of a sulfonamide), or a sulfamoylchloride (for formation of a sulfamide). Compounds of formula Ib can beprepared from compound Ia in the presence of a reducing reagent (e.g.,borane-THF complex or Lithium aluminum hydride/THF).

Alternatively, compounds of formula VIII can be prepared as described inScheme 2. Compounds of formula XIII can be prepared from intermediate V(outlined in Scheme 1) using a reducing reagent (e.g., sodiumborohydride). Conversion of the hydroxyl group in compound XIII tobromide XIV can be achieved using a brominating reagent (e.g., carbontetrabromide and triphenylphosphine). Compounds of formula XVI can beprepared by alkylating an appropriately protected glycine ester XV withbromide XIV in the presence of a strong base (e.g., lithiumbis(trimethylsilyl)amide) in THF at low temperature, preferably below50° C. Reagents of formula XV are either commercially available or canbe readily prepared by one skilled in the art. Amine intermediate XVIIcan be prepared by hydrolysis of XVI in a mild acidic condition (e.g.,citric acid in aqueous THF). Amine intermediate XVII can be protected asshown in compounds of formula VIII using a conventional method known toone skilled in the art.

EXAMPLES

The following examples serve to better illustrate, but not limit, someof the preferred embodiments of the invention.

Analytical HPLC and HPLC/MS Methods Employed in Characterization ofExamples.

Analytical HPLC was performed on Shimadzu LC10AS liquid chromatographs.

Analytical HPLC/MS was performed on Shimadzu LC10AS liquidchromatographs and Waters ZMD Mass Spectrometers using the followingmethods:

Method A. Linear Gradient of 0 to 100% Solvent B Over 4 min, with 1 minHold at 100% B

-   -   UV visualization at 220 nm    -   Column: Phenomenex Luna C18 4.6×50 mm    -   Flow rate: 4 ml/min

-   Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol

-   Solvent B: 0.1% trifluoroacetic acid, 90% methanol, 10% water    Method B. Linear Gradient of 0 to 100% Solvent B Over 8 min, with 3    min Hold at 100% B    -   UV visualization at 220 nm    -   Column: Phenomenex Luna C18 4.6×75 mm or Zorbax SB C18 4.6×75 mm    -   Flow rate: 2.5 ml/min

-   Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol

-   Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water    NMR Employed in Characterization of Examples.

¹H NMR spectra were obtained with Bruker or JOEL fourier transformspectrometers operating at the following frequencies: ¹H NMR: 400 MHz(Bruker), or 400 MHz (JOEL); ¹³C NMR: 100 MHz (Bruker), or 100 MHz(JOEL). Spectra data are reported as Chemical shift (multiplicity,number of hydrogens, coupling constants in Hz) and are reported in ppm(δ units) relative to either an internal standard (tetramethylsilane=0ppm) for ¹H NMR spectra, or are referenced to the residual solvent peak(2.49 ppm for CD₂HSOCD₃, 3.30 ppm for CD₂HOD, 7.24 ppm for CHCl₃, 39.7ppm for CD₃SOCD₃, 49.0 ppm for CD₃OD, 77.0 ppm for CDCl₃). All ¹³C NMRspectra were proton decoupled.

Example 1 Preparation of Benzyl2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ylcarbamate

1A. Preparation of Methyl2-(benzyloxycarbonylamino)-2-(diethoxyphosphoryl)acetate

The title compound was prepared from benzyl carbamate and 2-oxoaceticacid monohydrate following literature procedures.

1B. Preparation of 6-Phenylpyridin-3-amine

To a solution of 3-amino-6-bromopyridine (1.1 g, 6.4 mmol) in THF (7mL)-MeOH (7 mL) at RT was added phenylboronic acid (1.60 g, 12.8 mmol),PXPd (69 mg, 0.13 mmol), followed by K₂CO₃ (3.54 g, 25.6 mmol). Thereaction mixture was stirred at 70° C. in a preheated oil bath for 16 h.After cooling to RT, the reaction mixture was poured into water (10 mL),and the resultant mixture was extracted with EtOAc (3×40 mL). Thecombined organic layers were washed with saturated NaCl, dried (Na₂SO₄),filtered and concentrated. The resulting residue was purified by silicagel (40 g) column chromatography eluting with a gradient of EtOAc(30-100%) in hexane to give the title compound as an off-white solid(940 mg, 86%). LC/MS (method A): retention time=1.28 min, (M+H)⁺=171.

1C. Preparation of 2-Bromo-6-phenylpyridin-3-amine

To a solution of 1B (85 mg, 0.5 mmol) in DMF (1 mL) at RT was addedN-bromosuccinimide (89 mg, 0.5 mmol). The reaction was stirred at RT for16 h. After this time, no starting material was detected by LC-MS. Thereaction was diluted with water (10 mL) and extracted with EtOAc (3×10mL). The combined organic layers were washed with saturated NaCl, driedover Na₂SO₄, filtered, and evaporated under reduced pressure. Theresidue was purified by silica gel (10 g) column chromatography, elutingwith a gradient of EtOAc (0-60%) in hexane to give the title compound asa light brown foam (100 mg, 80%). LC/MS (method A): retention time=2.96min, (M+H)⁺=249. ¹H NMR (CDCl₃, 400 MHz): δ 7.80-7.91(m, 2H), 7.50 (d,J=8.2 Hz, 1H), 7.38-7.44 (m, 2H), 7.31-7.35 (m, 1H), 7.05 (d, J=8.2 Hz,1H), 4.15 (s, 2H).

1D. Preparation of tert-Butyl 2-bromo-6-phenylpyridin-3-ylcarbamate

To a solution of 1C (75 mg, 0.3 mmol) in THF (1 mL) at 0° C. was addedsodium bis(trimethylsilyl)amide (1 M solution in THF, 0.63 mL, 0.63mmol). After addition, the reaction was stirred at 0° C. for 5 min, andthen di-tert-butyl dicarbonate (72 mg, 0.33 mmol) was added in severalportions. After addition, the reaction was stirred at RT for 1 h, andthen diluted with water and neutralized by adding ice-cold 1N aqueousHCl to pH=6˜7. The resultant mixture was extracted with EtOAc (2×15 mL).The combined organic layers were washed with saturated NaCl, dried(Na₂SO₄), filtered and concentrated. The resulting residue was purifiedby silica gel (10 g) column chromatography eluting with a gradient ofEtOAc (0-40%) in hexane to give the title compound as a pink coloredsolid (82 mg, 78%). LC/MS (method A): retention time=4.04 min,(M+H-tBu))⁺=349.

1E. Preparation of tert-Butyl 2-formyl-6-phenylpyridin-3-ylcarbamate

A solution of 1D (1.75 g, 5 mmol) in dry THF (50 mL) under argon wascooled to −72° C. and treated dropwise with n-butyllithium (2.5 M inhexanes, 4 mL, 10 mmol) at such a rate so that the temperature did notexceed −65° C. Upon completion of the addition, the reaction was stirredat −72° C. for an additional hour. N-formyl piperidine (1.1 mL, 10 mmol)was added, and then the reaction was allowed to warm up to 0° C. andmaintained there for an hour. The solution was quenched by the additionof 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred atRT for 5 min, extracted with EtOAc (3×50 mL). The combined organiclayers were washed with saturated NaCl, dried over Na₂SO₄, filtered, andevaporated under reduced pressure. The residue was purified by silicagel (110 g) column chromatography, eluting with a gradient of EtOAc(0-30%) in hexane to give the title compound as a yellow solid (1.02 g,68%). LC/MS (method A): retention time=4.24 min, (M+H-tBu)⁺=243. ¹H NMR(CDCl₃, 400 MHz): δ 10.25 (s, 1H), 10.15 (s, 1H), 8.86 (d, J=9.0 Hz,1H), 8.00-8.02 (m, 2H), 7.87(d, J=9.0 Hz, 1H), 7.38-7.47 (m, 3H) 1.56(s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 197.93, 153.16, 151.18, 138.26,138.14, 136.51, 129.45, 129.27, 127.50, 126.78, 125.80, 82.03, 28.64.

1F. Preparation of (Z)-Methyl2-(benzyloxycarbonylamino)-3-(3-(tert-butoxycarbonylamino)-6-phenylpyridin-2-yl)acrylate

To a slurry of 60% of sodium hydride (110 mg, 2.76 mmol) in THF (8 mL)at 0° C. was added 1A (900 mg, 2.5 mmol) in several portions over 10min. The reaction mixture was then brought to RT for 20 min, then cooledagain at 0° C. A suspension of 1E (680 mg, 2.3 mmol) in THF (8 mL) wasadded over 10 min at 0° C., then the reaction was warmed up to RT. Afterstirring for 20 min, the reaction was quenched with water (30 mL). Theaqueous layer was extracted with EtOAc (50 mL×2). The combined EtOAcextracts were dried (Na₂SO₄), filtered and concentrated. The resultingresidue was purified by silica gel (40 g) column chromatography elutingwith a gradient of EtOAc (0-60%) in hexane to give the title compound asan white foam (105 mg, 9%). LC/MS (method A): retention time=4.16 min,(M+H)⁺=504.

1G. Preparation of Methyl2-(benzyloxycarbonylamino)-3-(3-(tert-butoxycarbonylamino)-6-phenylpyridin-2-yl)propanoate

A suspension of 1F (650 mg, 1.29 mmol) and 5 wt % platinum on activatedcarbon (500 mg) in THF (60 mL) and MeOH (60 mL) was stirred at RT underH₂ at 80 psi for 5 days. The reaction mixture was filtered through aCelite pad and the filtrate was concentrated. The residue was purifiedby silica gel (40 g) column chromatography eluting with a gradient ofEtOAc (0-60%) in hexane to give the title compound as a foam (110 mg,17%). LC/MS (method A): retention time=3.82 min, (M+H)⁺=506.

Intermediate 1G was also prepared using the following method (fromExample 1H to Example 1L):

1H. Preparation of tert-Butyl2-(hydroxymethyl)-6-phenylpyridin-3-ylcarbamate

To a solution of 1E (2.37 g, 7.94 mmol) in THF (10 mL) and ethanol (20mL) at 0° C. was added sodium borohydride (300 mg, 7.94 mmol) in severalportions. After addition, the reaction was stirred at 0° C. for 10 min,and no starting material was detected by LC-MS. The resultant mixturewas quenched with saturated aqueous NaHCO₃ (30 mL) and extracted withEtOAc (3×30 mL). The combined organic layers were washed with saturatedNaCl, dried (Na₂SO₄), filtered and concentrated. The resulting residuewas purified by silica gel (120 g) column chromatography eluting with aisocratic of 15% EtOAc in hexane to give the title compound as a whitesolid (2.25 g, 95%). LC/MS (method A): retention time=3.06 min,(M+H)⁺=301.

1I. Preparation of tert-Butyl2-(bromomethyl)-6-phenylpyridin-3-ylcarbamate

A solution of 1H (2.14 g, 7.13 mmol) in dry CH₂Cl₂ (10 mL) at RT wasadded carbon tetrabromide (2.84 g, 8.6 mmol), followed bytriphenylphophine (2.24 g, 8.6 mmol). The reaction was stirred at RT for30 min. No starting material was detected by LC-MS. The reaction waspurified by silica gel (120 g) column chromatography eluting with agradient of EtOAc (0-50%) in hexane to give the title compound as awhite solid (2.2 g, 85%). LC/MS (method A): retention time=3.76 min,(M+H)⁺=363.

1J. Preparation of Ethyl3-(3-(tert-butoxycarbonylamino)-6-phenylpyridin-2-yl)-2-(diphenylmethyleneamino)propanoate

To a solution of ethyl N-(diphenylmethelene) glycine ester (1.54 g, 5.78mmol) in THF (35 mL) at −72° C. under argon was added lithiumbis(trimethylsilyl)amide (1 M solution in THF, 5.5 mL, 5.5 mmol)dropwise. After addition, the yellowish solution was stirred at −10° C.for 1 h, then cooled to −72° C. (becoming a yellow suspension). To asolution of 1I (1.91 g, 5.26 mmol) in THF (10 mL) at −60° C. was addedthe anion suspension via a canula dropwise over 20 min. After addition,the yellow suspension was stirred at −50° C. for 15 min, then warmed upto RT and quenched with saturated aqueous NH₄Cl (30 mL). The aqueouslayer was extracted with EtOAc (50 mL×3). The combined EtOAc extractswere dried (Na₂SO₄), filtered and concentrated. The resulting residuewas purified by silica gel (110 g) column chromatography eluting with agradient of EtOAc (0-50%) in hexane to give the title compound as anwhite solid (2.2 g, 69%).

1K. Preparation of Ethyl2-amino-3-(3-(tert-butoxycarbonylamino)-6-phenylpyridin-2-yl)propanoate

A solution of 1J (2.1 g, 3.82 mmol) in THF (30 mL) and H₂O (30 mL) at RTwas added citric acid (5 g). The reaction was stirred at RT for 1 h.After this time, no starting material was detected by LC-MS. Thereaction mixture was extracted with Et₂O (3×90 mL). The organic layerswere combined and washed with 0.5 N citric acid (2×60 mL). The combinedaqueous layers were basified to pH 8 by using 1 N NaOH (dropwise), andthen extracted with Et₂O (3×90 mL). The combined Et₂O extracts weredried (Na₂SO₄), filtered and concentrated to give the title compound asa oil (1.24 g, 84%). LC/MS (method A): retention time=2.94 min,(M+H)⁺=386.

1L. Preparation of Ethyl2-(benzyloxycarbonylamino)-3-(3-(tert-butoxycarbonylamino)-6-phenylpyridin-2-yl)propanoate

To a solution of 1K (1.14 g, 2.96 mmol) in CH₃CN (15 mL) was addedN-(benzyloxy carbonyloxy)succinimide (819 mg, 3.25 mmol). The reactionwas stirred at RT for 16 h. After this time, no starting material wasdetected by LC-MS. The reaction was concentrated under reduced pressure.The resulting residue was purified by silica gel (110 g) columnchromatography eluting with a gradient of EtOAc (0-50%) in hexane togive the title compound as an white foam (1.50 g, 97%). LC/MS (methodA): retention time=3.63 min, (M+H)⁺=526.

1M. Preparation of Benzyl2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ylcarbamate

A solution of 1L (145 mg, 0.287 mmol) in TFA (1 mL) and CH₂Cl₂ (1 mL)was stirred at RT for 1 h. After this time, no starting material wasdetected by LC-MS. The reaction was concentrated under reduced pressure.The resulting residue was diluted with EtOAc (40 mL) and washed withsaturated aqueous NaHCO₃ (20 mL). The aqueous layer was extracted withEtOAc (20 mL×2). The combined organic layers were washed with saturatedNaCl, dried over Na₂SO₄, filtered and concentrated to give the titlecompound as a white solid (110 mg, 100%). LC/MS (method A): retentiontime=3.09 min, (M+H)⁺=374.

Example 2 Preparation ofN-(1-Benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)benzenesulfonamide

2A. Preparation of Benzyl1-benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ylcarbamate

To a solution of 1M (104 mg, 0.28 mmol) in DMF (2 mL) was added cesiumcarbonate (228 mg, 0.7 mmol), followed by benzyl bromide (0.1 mL, 0.84mmol). The reaction mixture was stirred at 50° C. for 30 min. Aftercooling to RT, water was added. The mixture was extracted with EtOAc(2×30 mL). The combined organic layers were washed with saturated NaCl,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby silica gel (40 g) column chromatography eluting with a gradient ofEtOAc (0-60%) in hexane to give the title compound as a white solid (101mg, 78%). LC/MS (method A): retention time=3.79 min, (M+H)⁺=464.

2B. Preparation of3-Amino-1-benzyl-6-phenyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one

To a solution of 2A (96 mg, 0.207 mmol) in THF (6 mL) and MeOH (6 mL) atRT was added palladium 5% wt on activated carbon (64 mg). The reactionmixture was stirred under a hydrogen balloon for 1 h. The reaction wasfiltered and the filtrate concentrated to give the title compound as afoam (68 mg, 100%). LC/MS (method A): retention time=2.65 min,(M+H)⁺=330.

2C. Preparation ofN-(1-Benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)benzenesulfonamide

To a solution of 2B (63 mg, 0.19 mmol) in CH₃CN (2 mL) at RT was addedDIPEA (50 μL, 0.285 mmol), followed by benzenesulfonyl chloride (27 μL,0.21 mmol). After 5 min, white precipitates formed. The reaction wasstirred for additional 15 min. The product was collected by filtrationand the solid washed with CH₃CN (2-3 mL) to give the title compound as awhite solid (62 mg, 70%). LC/MS (method A): RT=3.58 min, (M+H)⁺=470. ¹HNMR (CDCl₃, 400 MHz): δ 8.41 (d, J=7.4 Hz, 1H), 8.04 (d, J=7.3 Hz, 2H),7.96 (d, J=7.3 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.62-7.70 (m, 3H), 7.50(t, J=7.3 Hz, 2H), 7.44-7.47 (m, 2H), 7.25-7.44 (m, 5H), 5.16 (s, 2H),4.4-4.55 (m, 1H), 3.25-3.31 (m, 2H).

Example 3 Preparation of(R)-N-(1-Benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)benzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 2C using a Chiralpad AD column (20×250 mm, 10 μM chiralstationary phase) eluting with a mixed solvent (methanol:ethanol=1:1) ata flow rate of 14 mL/min HPLC (method B): 99% at 7.27 min. MS (ES): m/z470 [M+H]⁺. Chiral HPLC: 99% e.e.; retention time=10.69 min;(Conditions: Chiralpad AD column (4.6×250 mm, 10 μm chiral stationaryphase; eluting with EtOH-MeOH (1:1) for 30 min at 1 mL/min. UV detectionat 220 nm). ¹H NMR (DMSO₆, 400 MHz): δ 8.41 (d, J=7.4 Hz, 1H), 8.04 (d,J=7.3 Hz, 2H), 7.96 (d, J=7.3 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.62-7.70(m, 3H), 7.50 (t, J=7.3 Hz, 2H), 7.44-7.47 (m, 2H), 7.25-7.44 (m, 5H),5.16 (s, 2H), 4.4-4.55 (m, 1H), 3.25-3.31 (m, 2H).

Example 4 Preparation of(S)-N-(1-Benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)benzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 2C using a Chiralpad AD column (20×250 mm, 10 μM chiralstationary phase) eluting with a mixed solvent (methanol:ethanol=1:1) ata flow rate of 14 mL/min. HPLC (method B): 99% at 7.27 min. MS (ES): m/z470 [M+H]⁺. Chiral HPLC: 99% e.e.; retention time=17.00 min;(Conditions: Chiralpad AD column (4.6×250 mm, 10 μm chiral stationaryphase; eluting with EtOH-MeOH (1:1) for 30 min at 1 mL/min. UV detectionat 220 nm). ¹H NMR (DMSO₆, 400 MHz): δ 8.41 (d, J=7.4 Hz, 1H), 8.04 (d,J=7.3 Hz, 2H), 7.96 (d, J=7.3 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.62-7.70(m, 3H), 7.50 (t, J=7.3 Hz, 2H), 7.44-7.47 (m, 2H), 7.25-7.44 (m, 5H),5.16 (s, 2H), 4.4-4.55 (m, 1H), 3.25-3.31 (m, 2H).

Example 5 Preparation ofN-(1-Benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-3-fluorobenze

To a solution of 2B (59 mg, 0.18 mmol) in CH₃CN (2 mL) at RT was addedDIPEA (50 μL, 0.29 mmol), followed by 3-fluorobenzene-1-sulfonylchloride (41 mg, 0.21 mmol). After 5 min, white precipitates formed. Thereaction was stirred for additional 15 min. The product was collected byfiltration and the solid washed with CH₃CN (2-3 mL) to give the titlecompound as a white solid (70 mg, 80%). HPLC (method B): 99% at 7.41min. MS (ES): m/z 488 [M+H]⁺. ¹H NMR (DMSO₆, 400 MHz): δ 8.51 (d, J=7.9Hz, 1H), 7.95-8.01 (m, 2H), 7.69-7.79 (m, 3H), 7.58-7.66 (m, 1H),7.34-7.52 (m, 5H), 7.26-7.32 (m, 2H), 7.16-7.24 (m, 3H), 5.04 (dd,J₁=28.6 Hz, J₂=16.3 Hz, 2H), 4.60-4.70 (m, 1H), 3.20-3.35 (m, 2H).

Example 6 Preparation of(R)-N-(1-Benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-3-fluorobenzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 5 using a Chiralpad AD column (5×50 cm, 20 μM chiral stationaryphase) eluting with a mixed solvent (methanol:ethanol=1:1) at a flowrate of 50 mL/min. HPLC (method B): 99% at 7.42 min. MS (ES): m/z 488[M+H]⁺. Chiral HPLC: 99% e.e.; retention time=8.27 min; (Conditions:Chiralpad AD column (4.6×250 mm, 10 μm chiral stationary phase; elutingwith EtOH-MeOH (1:1) for 30 min at 1 mL/min. UV detection at 220 nm). ¹HNMR (DMSO₆, 400 MHz): δ 8.45 (s, 1H), 7.92 (d, J=7.5 Hz, 2H), 7.64-7.76(m, 3H), 7.52-7.62 (m, 1H), 7.36-7.46 (m, 3H), 7.28-7.34 (m, 2H), 7.22(t, J=7.9 Hz, 2H), 7.10-7.18 (m, 3H), 5.04 (dd, J₁=28.6 Hz, J₂=16.3 Hz,2H), 4.50-4.65 (m, 1H), 3.25-3.31 (m, 2H).

Example 7 Preparation of(S)-N-(1-Benzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-3-fluorobenzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 5 using a Chiralpad AD column (5×50 cm, 20 μM chiral stationaryphase) eluting with a mixed solvent (methanol:ethanol=1:1) at a flowrate of 50 mL/min. HPLC (method B): 99% at 7.42 min. MS (ES): m/z 488[M+H]⁺. Chiral HPLC: 99% e.e.; retention time=10.45 min; (Conditions:Chiralpad AD column (4.6×250 mm, 10 μm chiral stationary phase; elutingwith EtOH-MeOH (1:1) for 30 min at 1 mL/min. UV detection at 220 nm). ¹HNMR (DMSO₆, 400 MHz): δ 8.46 (s, 1H), 7.92 (d, J=7.5 Hz, 2H), 7.64-7.76(m, 3H), 7.52-7.62 (m, 1H), 7.36-7.46 (m, 3H), 7.28-7.34 (m, 2H), 7.22(t, J=7.9 Hz, 2H), 7.10-7.18 (m, 3H), 5.04 (dd, J₁=2.86 Hz, J₂=16.3 Hz,2H), 4.50-4.65 (m, 1H), 3.25-3.29 (m, 2H).

Example 8 Preparation ofN-(1-Benzyl-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)benzenesulfonamide

To a suspension of 2C (45 mg, 0.096 mmol) in THF (1 mL) at RT underargon was added borane-tetrahydrofuran complex (1 M solution in THF,0.48 mL, 0.48 mmol) dropwise. After the addition, the reaction became aclear solution. The reaction was allowed to stir at RT under argon for 1h. After this time, no starting material was detected by LC-MS. MeOH (1mL) was added carefully to the reaction and the mixture was stirred atRT for 60 min, then concentrated under reduced pressure. The resultingresidue was partitioned between CH₂Cl₂ (30 mL) and saturated aqueousNaHCO₃. The layers were separated. The aqueous layer was extracted withCH₂Cl₂ (20 mL). The combined organic layer were washed with saturatedNaCl, dried over Na₂SO₄, filtered and concentrated. The resultantresidue was dissolved in boiling CH₃CN (2 μL) and EtOAc (2 mL), and thenhexane (10 mL) was added. After cooling to RT. White precipitatesfoamed. The product was collected by filtration and washed with hexaneto give the title compound as a white solid (33 mg, 76%). HPLC (methodB): 99% at 5.62 min. MS (ES): m/z 456 [M+H]⁺. ¹H NMR (DMSO₆, 400 MHz): δ8.13 (d, J=6.2 Hz, 1H), 7.92-7.96 (m, 4H), 7.64-7.76 (m, 3H), 7.59 (d,J=8.6 Hz, 1H), 7.29-7.46 (m, 4H), 7.28-7.34 (m, 4H), 7.00 (d, J=8.6 Hz,1H), 4.54 (dd, J₁=48.9 Hz, J₂=16.5 Hz, 2H), 3.40-3.45 (m, 1H),3.36-3.40(m, 1H), 3.25-3.29 (m, 1H), 2.90-3.01(m, 2H).

Example 9 Preparation of(R)-N-(1-Benzyl-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)benzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 8 using a Chiralpad AD column (5×50 cm, 20 μM chiral stationaryphase) eluting with 40% isopropanol in heptane at a flow rate of 50mL/min. HPLC (method B): 99% at 5.59 min. MS (ES): m/z 456 [M+H]⁺.Chiral HPLC: 99% e.e.; retention time=10.72 min; (Conditions: ChiralpadAD column (4.6×250 mm, 10 μm chiral stationary phase; eluting with 20%isopropanol+20% MeOH+60% heptane for 30 min at 1 mL/min.UV detection at220 nm). ¹H NMR (DMSO₆, 400 MHz): δ 8.05 (d, J=6.2 Hz, 1H), 7.80-7.92(m, 4H), 7.56-7.68 (m, 3H), 7.53 (d, J=8.8 Hz, 1H), 7.27-7.40 (m, 4H),7.18-7.28 (m, 4H), 6.92 (d, J=8.8 Hz, 1H), 4.50 (dd, J₁=48.9 Hz, J₂=16.9Hz, 2H), 3.56-3.70 (m, 1H), 3.36-3.40(m, 1H), 3.15-3.25 (m, 1H),2.85-2.97 (m, 2H).

Example 10 Preparation of(S)-N-(1-Benzyl-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)benzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 8 using a Chiralpad AD column (5×50 cm, 20 μM chiral stationaryphase) eluting with 40% isopropanol in heptane at a flow rate of 50mL/min. HPLC (method B): 99% at 5.62 min. MS (ES): m/z 456 [M+H]⁺.Chiral HPLC: 99% e.e.; retention time=15.80 min; (Conditions: ChiralpadAD column (4.6×250 mm, 10 μm chiral stationary phase; eluting with 20%isopropanol+20% MeOH′+60% heptane for 30 min at 1 mL/min.UV detection at220 nm). ¹H NMR (DMSO₆, 400 MHz): δ 8.05 (d, J=6.2 Hz, 1H), 7.80-7.92(m, 4H), 7.56-7.68 (m, 3H), 7.53 (d, J=8.8 Hz, 1H), 7.27-7.40 (m, 4H),7.18-7.28 (m, 4H), 6.92 (d, J=8.8 Hz, 1H), 4.50 (dd, J₁=48.9 Hz, J=16.9Hz, 2H), 3.56-3.70 (m, 1H), 3.36-3.40(m, 1H), 3.15-3.25 (m, 1H),2.85-2.97 (m, 2H).

Example 11 Preparation ofN-(1-Benzyl-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-3-fluorobenzenesulfonamide

To a suspension of 5 (43 mg, 0.088 mmol) in THF (1 mL) at RT under argonwas added borane-tetrahydrofuran complex (1 M solution in THF, 0.44 mL,0.44 mmol) dropwise. After the addition, the reaction became a clearsolution. The reaction was allowed to stir at RT under argon for 1 h.After this time, no starting material was detected by LC-MS. MeOH (1 mL)was added carefully to the reaction and the reaction mixture was stirredat RT for 60 min, then concentrated under reduced pressure. Theresulting residue was partitioned between CH₂Cl₂ (30 mL) and saturatedaqueous NaHCO₃. The layers were separated. The aqueous layer wasextracted with CH₂Cl₂ (20 mL). The combined organic layer were washedwith saturated NaCl, dried over Na₂SO₄, filtered and concentrated. Theresultant residue was dissolved in boiling CH₃CN (2 mL) and EtOAc (2mL), and then hexane (10 mL) was added. After cooling to RT, whiteprecipitates foamed. The product was collected by filtration and washedwith hexane to give the title compound as a off-white solid (30 mg,71%). HPLC (method B): 99% at 5.87 min. MS (ES): m/z 474 [M+H]⁺. ¹H NMR(DMSO₆, 400 MHz): δ 8.16 (d, J=6.6 Hz, 1H), 7.82-7.90 (m, 2H), 7.60-7.72(m, 3H), 7.48-7.54 (m, 2H), 7.27-7.40 (m, 4H), 7.18-7.28 (m, 4H), 6.92(d, J=8.8 Hz, 1H), 4.50 (dd, J₁=58.0 Hz, J₂=16.9 Hz, 2H), 3.66-3.76 (m,1H), 3.36-3.44 (m, 1H), 3.17-3.25 (m, 1H), 2.78-3.00 (m, 2H).

Example 12 Preparation of(R)-(1-Benzyl-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-3-fluorobenzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 11 using a Chiralpad AD column (5×50 cm, 20 μM chiral stationaryphase) eluting with a mixed solvent (isopropanol:methanol:heptane=1:1:3)at a flow rate of 50 mL/min. HPLC (method B): 99% at 5.87 min. MS (ES):m/z 474 [M+H]⁺. Chiral HPLC: 99% e.e.; retention time=8.94 min;(Conditions: Chiralpad AD column (4.6×250 mm, 10 μm chiral stationaryphase; eluting with 20% isopropanol+20% MeOH′+60% heptane for 30 min at1 mL/min.UV detection at 220 nm). ¹H NMR (DMSO₆, 400 MHz): δ 8.16 (d,J=6.2 Hz, 1H), 7.87 (d, J=7.5 Hz, 2H), 7.60-7.74 (m, 3H), 7.48-7.54 (m,2H), 7.27-7.40 (m, 4H), 7.18-7.28 (m, 4H), 6.92 (d, J=8.8 Hz, 1H), 4.50(dd, J₁=58.0 Hz, J₂=16.9 Hz, 2H), 3.66-3.76 (m, 1H), 3.36-3.44 (m, 1H),3.17-3.25 (m, 1H), 2.78-3.00 (m, 2H).

Example 13 Preparation of(S)-N-(1-Benzyl-6-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)-3-fluorobenzenesulfonamide

The title compound was obtained via chiral chromatographic separation ofracemic 11 using a Chiralpad AD column (5×50 cm, 20 μM chiral stationaryphase) eluting with a mixed solvent (isopropanol:methanol:heptane=1:1:3)at a flow rate of 50 mL/min. HPLC (method B): 99% at 5.85 min. MS (ES):m/z 474 [M+H]⁺. Chiral HPLC: 99% e.e.; retention time=15.01 min;(Conditions: Chiralpad AD column (4.6×250 mm, 10 μm chiral stationaryphase; eluting with 20% isopropanol+20% MeOH+60% heptane for 30 min at 1mL/min.UV detection at 220 nm). ¹H NMR (DMSO₆, 400 MHz): δ 8.16 (d,J=6.2 Hz, 1H), 7.82-7.90 (m, 2H), 7.60-7.74 (m, 3H), 7.48-7.54 (m, 2H),7.27-7.40 (m, 4H), 7.18-7.28 (m, 4H), 6.92 (d, J=8.8 Hz, 1H), 4.50 (dd,J₁=58.0 Hz, J₂=16.9 Hz, 2H), 3.66-3.76 (m, 1H), 3.36-3.44 (m, 1H),3.17-3.25 (m, 1H), 2.78-3.00 (m, 2H).

Biological Evaluation

Cannabinoid Receptor Binding Assay

Radioligand binding studies were conducted in membranes prepared fromChinese Hamster Ovary (CHO) cells that over-express recombinant humanCB-1 (CHO-CB-1 cells). Total assay volume for the binding studies was100 μl. 5 μg of membranes were brought up to a final volume of 95 μlwith Binding Buffer (25 mM HEPES, 150 mM NaCl, 2.5 mM CaCl₂, 1 mM MgCl₂,0.25% BSA). The diluted membranes were preincubated with a compound orDMSO vehicle. The binding reaction was initiated by the addition of 2 nMfinal ³H—CP-55,940 (120 Ci/mmol) and proceeded for 2.5 hours at roomtemperature. The binding reaction was terminated by transferring thereaction to GF/B 96 well plates (presoaked with 0.3% polyethylenimine)using a Packard Cell Harvester. The filter was washed with 0.25×PBS, 30μl MicroScint was added per well, and the bound radiolabel wasquantitated by scintillation counting on a Packard TopCountScintillation Counter. The CB-2 radioligand binding assay was conductedidentically except that the membranes from CHO-CB-2 cells were used.

For a compound to be considered a CB-1 antagonist, the compound mustpossess a CB-1 receptor binding affinity Ki less than 13000 nM. Asdetermined by the assay described above, the CB-1 receptor binding K_(i)values of the working Examples fall within the range of 0.01 nM to 10000nM.

Cannabinoid Receptor Functional Activity Assay

Functional CB-1 inverse agonist activity of test compounds wasdetermined in CHO-CB-1 cells using a cAMP accumulation assay. CHO-CB-1cells were grown in 96 well plates to near confluence. On the day of thefunctional assay, growth medium was aspirated and 100 of Assay Buffer(PBS plus 25 mM HEPES/0.1 mM 3-isobutyl-1-methylxanthine/0.1% BSA) wasadded. Compounds were added to the Assay buffer diluted 1:100 from 100%DMSO and allowed to preincubate for 10 minutes prior to addition of 5 uMforskolin. The mixture was allowed to proceed for 15 minutes at roomtemperature and was terminated by the addition of 0.1 N HCl. The totalintracellular cAMP concentration was quantitated using the Amersham cAMPSPA kit.

Utilities and Combinations

Utilities

The compounds of the present invention are cannabinoid receptormodulators, and include compounds which are, for example, selectiveagonists, partial agonists, inverse agonists, antagonists or partialantagonists of the cannabinoid receptor. Accordingly, the compounds ofthe present invention may be useful for the treatment or prevention ofdiseases and disorders associated with G-protein coupled cannabinoidreceptor activity. Preferably, compounds of the present inventionpossess activity as antagonists or inverse agonists of the CB-1receptor, and may be used in the treatment of diseases or disordersassociated with the activity of the CB-1 receptor.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to metabolic andeating disorders as well as conditions associated with metabolicdisorders, (e.g., obesity, diabetes, arteriosclerosis, hypertension,polycystic ovary disease, cardiovascular disease, osteoarthritis,dermatological disorders, hypertension, insulin resistance,hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleepdisorders, hyperlipidemic conditions, bulimia nervosa and compulsiveeating disorders) or psychiatric disorders, such as substance abuse,depression, anxiety, mania and schizophrenia. These compounds could alsobe used for the improvement of cognitive function (e.g., the treatmentof dementia, including Alzheimer's disease, short term memory loss andattention deficit disorders); neurodegenerative disorders (e.g.,Parkinson's Disease, cerebral apoplexy and craniocerebral trauma) andhypotension (e.g., hemorrhagic and endotoxin-induced hypotension). Thesecompounds could also be used for treatment of catabolism in connectionwith pulmonary dysfunction and ventilator dependency; treatment ofcardiac dysfunction (e.g., associated with valvular disease, myocardialinfarction, cardiac hypertrophy or congestive heart failure); andimprovement of the overall pulmonary function; transplant rejection;rheumatoid arthritis; multiple sclerosis; inflammatory bowel disease;lupus; graft vs. host disease; T-cell mediated hypersensitivity disease;psoriasis; asthma; Hashimoto's thyroiditis; Guillain-Barre syndrome;cancer; contact dermatitis; allergic rhinitis; and ischemic orreperfusion injury.

Compounds useful in the treatment of appetitive or motivationaldisorders regulate desires to consume sugars, carbohydrates, alcohol ordrugs and more generally to regulate the consumption of ingredients withhedonic value. In the present description and in the claims, appetitivedisorders are understood as meaning: disorders associated with asubstance and especially abuse of a substance and/or dependency on asubstance, disorders of eating behaviors, especially those liable tocause excess weight, irrespective of its origin, for example: bulimianervosa, craving for sugars. The present invention therefore furtherrelates to the use of a CB-1 receptor antagonist or inverse agonist forthe treatment of bulimia and obesity, including obesity associated withtype II diabetes (non-insulin-dependent diabetes), or more generally anydisease resulting in the patient becoming overweight. Obesity, asdescribed herein, is defined by a body mass index (kg/m²) of at least26. It may be due to any cause, whether genetic or environmental,including overeating and bulimia, polycycstic ovary disease,craniopharyngeoma, Prader-Willi Syndrome, Frohlich's Syndrome, Type IIdiabetes, growth hormone deficiency, Turner's Syndrome and otherpathological states characterized by reduced metabolic activity orreduced energy expenditure. As used with reference to the utilitiesdescribed herein, the term “treating” or “treatment” encompassesprevention, partial alleviation, or cure of the disease or disorder.Further, treatment of obesity is expected to prevent progression ofmedical covariants of obesity, such as arteriosclerosis, Type IIdiabetes, polycystic ovary disease, cardiovascular disease,osteoarthritis, dermatological disorders, hypertension, insulinresistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasisand sleep disorders.

Compounds in the present invention may also be useful in treatingsubstance abuse disorders, including substance dependence or abusewithout physiological dependence. Substances of abuse include alcohol,amphetamines (or amphetamine-like substances), caffeine, cannabis,cocaine, hallucinogens, inhalents, nicotine, opioids, phencyclidine (orphencyclidine-like compounds), sedative-hypnotics or benzodiazepines,and other (or unknown) substances and combinations of the above. Theterms “substance abuse disorders” also includes drug or alcoholwithdrawal syndromes and substance-induced anxiety or mood disorder withonset during withdrawal.

Compounds in the present invention may be useful in treating memoryimpairment and cognitive disorders. The condition of memory impairmentis manifested by impairment of the ability to learn new informationand/or the inability to recall previously learned information. Memoryimpairment is a primary symptom of dementia and can also be a symptomassociated with such diseases as Alzheimer's disease, schizophrenia,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head traumaas well as age-related cognitive decline. Dementias are diseases thatinclude memory loss and additional intellectual impairment separate frommemory. Cannabinoid receptor modulators may also be useful in treatingcognitive impairments related to attentional deficits, such as attentiondeficit disorder.

Compounds in the present invention may also be useful in treatingdiseases associated with dysfunction of brain dopaminergic systems, suchas Parkinson's Disease and substance abuse disorders. Parkinsons'sDisease is a neurodegenerative movement disorder characterized bybradykinesia and tremor.

As modulators of the cannabinoid receptor, the compounds of the presentinvention are further useful for the treatment and prevention ofrespiratory diseases and disorders. Respiratory diseases for whichcannabinoid receptor modulators are useful include, but are not limitedto, chronic pulmonary obstructive disorder, emphysema, asthma, andbronchitis. In addition, cannabinoid receptor modulators block theactivation of lung epithelial cells by moeties such as allergic agents,inflammatory cytokines or smoke, thereby limiting release of mucin,cytokines, and chemokines, or selectively inhibiting lung epithelialcell activation.

Moreover, the compounds employed in the present invention may stimulateinhibitory pathways in cells, particularly in leukocytes, lungepithelial cells, or both, and are thus useful in treating suchdiseases. “Leukocyte activation” is defined herein as any or all of cellproliferation, cytokine production, adhesion protein expression, andproduction of inflammatory mediators. “Epithelial cell activation” isdefined herein as the production of any or all of mucins, cytokines,chemokines, and adhesion protein expression.

Use of the compounds of the present invention for treating leukocyteactivation-associated disorders is exemplified by, but is not limitedto, treating a range of disorders such as: transplant (such as organtransplant, acute transplant, xenotransplant or heterograft or homograft(such as is employed in burn treatment)) rejection; protection fromischemic or reperfusion injury such as ischemic or reperfusion injuryincurred during organ transplantation, myocardial infarction, stroke orother causes; transplantation tolerance induction; arthritis (such asrheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiplesclerosis; respiratory and pulmonary diseases including but not limitedto chronic obstructive pulmonary disease (COPD), emphysema, bronchitis,and acute respiratory distress syndrome (ARDS); inflammatory boweldisease, including ulcerative colitis and Crohn's disease; lupus(systemic lupus erythematosis); graft vs. host disease; T-cell mediatedhypersensitivity diseases, including contact hypersensitivity,delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiacdisease); psoriasis; contact dermatitis (including that due to poisonivy); Hashimoto's thyroiditis; Sjogren's syndrome; AutoimmuneHyperthyroidism, such as Graves' Disease; Addison's disease (autoimmunedisease of the adrenal glands); Autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome); autoimmune alopecia;pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barresyndrome; other autoimmune diseases; glomerulonephritis; serum sickness;urticaria; allergic diseases such as respiratory allergies (asthma,hayfever, allergic rhinitis) or skin allergies; scleracierma; mycosisfungoides; acute inflammatory and respiratory responses (such as acuterespiratory distress syndrome and ischemia/reperfusion injury);dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema;Behcet's disease; Pustulosis palmoplanteris; Pyoderma gangrenum;Sezary's syndrome; a topic dermatitis; systemic sclerosis; and morphea.The term “leukocyte activation-associated” or “leukocyte-activationmediated” disease as used herein includes each of the above referenceddiseases or disorders. In a particular embodiment, the compounds of thepresent invention are useful for treating the aforementioned exemplarydisorders irrespective of their etiology. The combined activity of thepresent compounds towards monocytes, macrophages, T-cells, etc. may beuseful in treating any of the above-mentioned disorders.

Cannabinoid receptors are important in the regulation of Fc gammareceptor responses of monocytes and macrophages. Compounds of thepresent invention inhibit the Fc gamma dependent production of TNF alphain human monocytes/macrophages. The ability to inhibit Fc gamma receptordependent monocyte and macrophage responses results in additionalanti-inflammatory activity for the present compounds. This activity isespecially of value, for example, in treating inflammatory diseases suchas arthritis or inflammatory bowel disease. In particular, the presentcompounds are useful for treating autoimmune glomerulonephritis andother instances of glomerulonephritis induced by deposition of immunecomplexes in the kidney that trigger Fc gamma receptor responses leadingto kidney damage.

Cannabinoid receptors are expressed on lung epithelial cells. Thesecells are responsible for the secretion of mucins and inflammatorycytokines/chemokines in the lung and are thus intricately involved inthe generation and progression of respiratory diseases. Cannabinoidreceptor modulators regulate both the spontaneous and the stimulatedproduction of both mucins and cytokines. Thus, such compounds are usefulin treating respiratory and pulmonary diseases including, COPD, ARDS,and bronchitis.

Further, cannabinoid receptors may be expressed on gut epithelial cellsand hence regulate cytokine and mucin production and may be of clinicaluse in treating inflammatory diseases related to the gut. Cannabinoidreceptors are also expressed on lymphocytes, a subset of leukocytes.Thus, cannabinoid receptor modulators will inhibit B and T-cellactivation, proliferation and differentiation. Thus, such compounds willbe useful in treating autoimmune diseases that involve either antibodyor cell mediated responses such as multiple sclerosis and lupus.

In addition, cannabinoid receptors regulate the Fc epsilon receptor andchemokine induced degranulation of mast cells and basophils. These playimportant roles in asthma, allergic rhinitis, and other allergicdisease. Fc epsilon receptors are stimulated by IgE-antigen complexes.Compounds of the present invention inhibit the Fc epsilon induceddegranulation responses, including the basophil cell line, RBL. Theability to inhibit Fc epsilon receptor dependent mast cell and basophilresponses results in additional anti-inflammatory and anti-allergicactivity for the present compounds. In particular, the present compoundsare useful for treating asthma, allergic rhinitis, and other instancesof allergic disease.

Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-obesity agents; anti-diabeticagents, appetite suppressants; cholesterol/lipid-lowering agents,HDL-raising agents, cognition enhancing agents, agents used to treatneurodegeneration, agents used to treat respiratory conditions, agentsused to treat bowel disorders, anti-inflammatory agents; anti-anxietyagents; anti-depressants; anti-hypertensive agents; cardiac glycosides;and anti-tumor agents.

Such other therapeutic agent(s) may be administered prior to,simultaneously with, or following the administration of the cannabinoidreceptor modulators in accordance with the invention.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include melanocortin receptor (MC4R)agonists, melanin-concentrating hormone receptor (MCHR) antagonists,growth hormone secretagogue receptor (GHSR) antagonists, galaninreceptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists,and other Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonsist,NPY2 and NPY4 modulators, corticotropin releasing factor agonists,histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gammamodulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC)inihibitors, 11-β-HSD-1 inhibitors, adinopectin receptor modulators;beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355(Merck), or CP331648 (Pfizer) or other known beta 3 agonists asdisclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983and 5,488,064, a thyroid receptor beta modulator, such as a thyroidreceptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353(KaroBio), a lipase inhibitor, such as orlistat or ATL-962 (Alizyme),serotonin receptor agonists, (e.g., BVT-933 (Biovitrum)), monoaminereuptake inhibitors or releasing agents, such as fenfluramine,dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline,chlorphentermine, cloforex, clortermine, picilorex, sibutramine,dexamphetamine, phentermine, phenylpropanolamine or mazindol, anorecticagents such as topiramate (Johnson & Johnson), CNTF (ciliaryneurotrophic factor)/Axokine® (Regeneron), BDNF (brain-derivedneurotrophic factor), leptin and leptin receptor modulators, orcannabinoid-1 receptor antagonists, such as SR-141716 (Sanofi) orSLV-319 (Solvay).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: insulin secretagogues orinsulin sensitizers, which may include biguanides, sulfonyl ureas,glucosidase inhibitors, aldose reductase inhibitors, PPAR γ agonistssuch as thiazolidinediones, PPAR α agonists (such as fibric acidderivatives), PPAR δ antagonists or agonists, PPAR α/γ dual agonists,11-β-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, aswell as insulin, and/or glucagon-like peptide-1 (GLP-1), GLP-1 agonist,and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor).

The antidiabetic agent may be an oral antihyperglycemic agent preferablya biguanide such as metformin or phenformin or salts thereof, preferablymetformin HCl. Where the antidiabetic agent is a biguanide, thecompounds of the present invention will be employed in a weight ratio tobiguanide within the range from about 0.001:1 to about 10:1, preferablyfrom about 0.01:1 to about 5:1.

The antidiabetic agent may also preferably be a sulfonyl urea such asglyburide (also known as glibenclamide), glimepiride (disclosed in U.S.Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the beta-cells, with glyburide and glipizidebeing preferred, which may be administered in the same or in separateoral dosage forms. The oral antidiabetic agent may also be a glucosidaseinhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) ormiglitol (disclosed in U.S. Pat. No. 4,639,436), which may beadministered in the same or in a separate oral dosage forms.

The compounds of the present invention may be employed in combinationwith a PPAR γ agonist such as a thiazolidinedione oral anti-diabeticagent or other insulin sensitizers (which has an insulin sensitivityeffect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of the present invention may be employed with a PPARα/γdual agonist such as MK-767/KRP-297 (Merck/Kyorin; as described in, K.Yajima, et. al., Am. J. Physiol. Endocrinol. Metab., 284: E966-E971(2003)), AZ-242 (tesaglitazar; Astra-Zeneca; as described in B. Ljung,et. al., J. Lipid Res., 43, 1855-1863 (2002)); muraglitazar; or thecompounds described in U.S. Pat. No. 6,414,002.

The compounds of the present invention may be employed in combinationwith anti-hyperlipidemia agents, or agents used to treatarteriosclerosis. An example of an hypolipidemic agent would be an HMGCoA reductase inhibitor which includes, but is not limited to,mevastatin and related compounds as disclosed in U.S. Pat. No.3,983,140, lovastatin (mevinolin) and related compounds as disclosed inU.S. Pat. No. 4,231,938, pravastatin and related compounds such asdisclosed in U.S. Pat. No. 4,346,227, simvastatin and related compoundsas disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoAreductase inhibitors which may be employed herein include, but are notlimited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772,cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080,atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) oritavastatin), disclosed in U.S. Pat. No. 5,011,930,Shionogi-Astra/Zeneca rosuvastatin (visastatin (ZD-4522)) disclosed inU.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S.Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. Inaddition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller, et al., J. Med. Chem., 31,1869-1871 (1998) including isoprenoid (phosphinyl-methyl)phosphonates aswell as other known squalene synthetase inhibitors, for example, asdisclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S.A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., CurrentPharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano, et al., J. Med. Chem., 20, 243-249 (1977), the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 98, 1291-1293 (1976),phosphinylphosphonates reported by McClard, R. W. et al., J. Am. Chem.Soc., 109, 5544 (1987) and cyclopropanes reported by Capson, T. L., PhDdissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp 16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) andcholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The other hypolipidemic agent may be an ACAT inhibitor (which also hasanti-atherosclerosis activity) such as disclosed in, Drugs of theFuture, 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 iseffective in the prevention and regression of aortic fatty streak areain hamsters”, Nicolosi et al., Atherosclerosis (Shannon, Irel), 137 (1),77-85 (1998); “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev., 16 (1), 16-30 (1998); “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al., Bioorg. Med. Chem. Lett, 6 (1), 47-50 (1996); “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al.,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways, 173-98 (1995), Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al., Curr. Med. Chem., 1 (3), 204-25 (1994); “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)-methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al., Chemtracts: Org. Chem., 8(6), 359-62 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd), as wellas F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

The hypolipidemic agent may be an upregulator of LDL receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973(1998).

The other lipid agent or lipid-modulating agent may be a cholesteryltransfer protein inhibitor (CETP) such as Pfizer's CP-529,414 as well asthose disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496,and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

The other lipid agent also includes a phytoestrogen compound such asdisclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterolabsorption inhibitor such as disclosed in EP 675714; an HDL upregulatorsuch as an LXR agonist, a PPAR α-agonist and/or an FXR agonist; an LDLcatabolism promoter such as disclosed in EP 1022272; a sodium-protonexchange inhibitor such as disclosed in DE 19622222; an LDL-receptorinducer or a steroidal glycoside such as disclosed in U.S. Pat. No.5,698,527 and GB 2304106; an anti-oxidant such as beta-carotene,ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 aswell as Vitamin C and an antihomocysteine agent such as folic acid, afolate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as disclosed inWO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthaseinhibitor, or a lanosterol demethylase inhibitor as disclosed in WO97/48701; a PPAR δ agonist for treating dyslipidemia; or a sterolregulating element binding protein-I (SREBP-1) as disclosed in WO2000/050574, for example, a sphingolipid, such as ceramide, or neutralsphingomyelenase (N-SMase) or fragment thereof. Preferred hypolipidemicagents are pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin, pitavastatin and rosuvastatin, as well as niacin and/orcholestagel.

The compounds of the present invention may be employed in combinationwith anti-hypertensive agents. Examples of suitable anti-hypertensiveagents for use in combination with the compounds of the presentinvention include beta adrenergic blockers, calcium channel blockers(L-type and/or T-type; e.g. diltiazem, verapamil, nifedipine, amlodipineand mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors,ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.

Cannbinoid receptor modulators could be useful in treating otherdiseases associated with obesity, including sleep disorders. Therefore,the compounds described in the present invention could be used incombination with therapeutics for treating sleep disorders. Examples ofsuitable therapies for treatment of sleeping disorders for use incombination with the compounds of the present invention includemelatonin analogs, melatonin receptor antagonists, ML 1 B agonists, GABAreceptor modulators; NMDA receptor modulators, histamine-3 (H3) receptormodulators, dopamine agonists and orexin receptor modulators.

Cannabinoid receptor modulators may reduce or ameliorate substance abuseor addictive disorders. Therefore, combination of cannabinoid receptormodulators with agents used to treat addictive disorders may reduce thedose requirement or improve the efficacy of current addictive disordertherapeutics. Examples of agents used to treat substance abuse oraddictive disorders are: selective serotonin reuptake inhibitors (SSRI),methadone, buprenorphine, nicotine and bupropion.

Cannabinoid receptor modulators may reduce anxiety or depression;therefore, the compounds described in this application may be used incombination with anti-anxiety agents or antidepressants. Examples ofsuitable anti-anxiety agents for use in combination with the compoundsof the present invention include benzodiazepines (e.g., diazepam,lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam,chlorazepate, halazepam and prazepam), 5HT1A receptor agonists (e.g.,buspirone, flesinoxan, gepirone and ipsapirone), and corticotropinreleasing factor (CRF) antagonists.

Examples of suitable classes of anti-depressants for use in combinationwith the compounds of the present invention include norepinephrinereuptake inhibitors (tertiary and secondary amine tricyclics), selectiveserotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine,paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs)(isocarboxazid, phenelzine, tranylcypromine, selegiline), reversibleinhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin andnorepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropinreleasing factor (CRF) receptor antagonists, alpah-adrenoreceptorantagonists, and atypical antidepressants (bupropion, lithium,nefazodone, trazodone and viloxazine).

The combination of a conventional antipsychotic drug with a CB-1receptor antagonist could also enhance symptom reduction in thetreatment of psychosis or mania. Further, such a combination couldenable rapid symptom reduction, reducing the need for chronic treatmentwith antipsychotic agents. Such a combination could also reduce theeffective antipsychotic dose requirement, resulting in reducedprobability of developing the motor dysfunction typical of chronicantipsychotic treatment.

Examples of suitable antipsychotic agents for use in combination withthe compounds of the present invention include the phenothiazine(chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine), thioxanthine(chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine,olanzepine and aripiprazole), butyrophenone (haloperidol),dipheyylbutylpiperidine (pimozide) and indolone (molindolone) classes ofantipsychotic agents. Other antipsychotic agents with potentialtherapeutic value in combination with the compounds in the presentinvention include loxapine, sulpiride and risperidone.

Combination of the compounds in the present invention with conventionalantipsychotic drugs could also provide an enhanced therapeutic effectfor the treatment of schizophrenic disorders, as described above formanic disorders. As used here, schizophrenic disorders include paranoid,disorganized, catatonic, undifferentiated and residual schizophrenia,schizophreniform disorder, shcizoaffective disorder, delusionaldisorder, brief psychotic disorder and psychotic disorder not specified.Examples of suitable antipsychotic drugs for combination with thecompounds in the present invention include the antipsychotics mentionedabove, as well as dopamine receptor antagonists, muscarinic receptoragonists, 5HT2A receptor antagonists and 5HT2A/dopamine receptorantagonists or partial agonists (e.g., olanzepine, aripiprazole,risperidone, ziprasidone).

The compounds described in the present invention could be used toenhance the effects of cognition-enhancing agents, such asacetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-1agonists (e.g., milameline), nicotinic agonists, glutamic acid receptor(AMPA and NMDA) modulators, and nootropic agents (e.g., piracetam,levetiracetam). Examples of suitable therapies for treatment ofAlzheimer's disease and cognitive disorders for use in combination withthe compounds of the present invention include donepezil, tacrine,revastigraine, 5HT6, gamma secretase inhibitors, beta secretaseinhibitors, SK channel blockers, Maxi-K blockers, and KCNQs blockers.

The compounds described in the present invention could be used toenhance the effects of agents used in the treatment of Parkinson'sDisease. Examples of agents used to treat Parkinson's Disease include:levadopa with or without a COMT inhibitor, antiglutamatergic drugs(amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan,opiate antagonists, such as naltrexone, other dopamine agonists ortransportor modulators, such as ropinirole, or pramipexole orneurotrophic factors such as glial derived neurotrophic factor (GDNF).

The compounds described in the present invention could be used incombination with suitable anti-inflammatory agents. Examples of suitableanti-inflammatory agents for use in combination with the compounds ofthe present invention include prednisone, dexamethasone, cyclooxygenaseinhibitors (i.e., COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin,indomethacin, ibuprofen, piroxicam, Naproxene®, Celebrex®, Vioxx®),CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, IMPDHinhibitors, such as mycophenolate (CellCept®), integrin antagonists,alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors,interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF)antagonists (e.g., infliximab, OR1384, including TNF-alpha inhibitors,such as tenidap, anti-TNF antibodies or soluble TNF receptor such asetanercept (Enbrel®), rapamycin (sirolimus or Rapamune) and leflunomide(Arava)), prostaglandin synthesis inhibitors, budesonide, clofazimine,CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activatedprotein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKKinhibitors, and therapies for the treatment of irritable bowel syndrome(e.g., Zelnorm® and Maxi-K® openers such as those disclosed in U.S. Pat.No. 6,184,231 B1).

Exemplary of such other therapeutic agents which may be used incombination with cannabinoid receptor modulators include the following:cyclosporins (e.g., cyclosporin A), anti-IL-2 receptor (Anti-Tac),anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86,monoclonal antibody OKT3, agents blocking the interaction between CD40and gp39, such as antibodies specific for CD40 and/or gp39 (i.e.,CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappaB function, such as deoxyspergualin (DSG), gold compounds,antiproliferative agents such as methotrexate, FK506 (tacrolimus,Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine andcyclophosphamide, anticytokines such as antiIL-4 or IL-4 receptor fusionproteins and PDE 4 inhibitors such as Ariflo, and the PTK inhibitorsdisclosed in the following U.S. patent applications, incorporated hereinby reference in their entirety: Ser. No. 09/097,338, filed Jun. 15,1998; Ser. No. 09/094,797, filed Jun. 15, 1998; Ser. No. 09/173,413,filed Oct. 15, 1998; and Ser. No. 09/262,525, filed Mar. 4, 1999. Seealso the following documents and references cited therein andincorporated herein by reference: Hollenbaugh, D., et al., “CleavableCD40Ig Fusion Proteins and the Binding to Sgp39”, J. Immunol. Methods(Netherlands), 188 (1), pp. 1-7 (Dec. 15, 1995); Hollenbaugh, D., etal., “The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Isa Ligand for the CD40 Receptor: Expression of a Soluble Form of Gp39with B Cell Co-Stimulatory Activity”, EMBO J (England), 11 (12), pp.4313-4321 (December 1992); and Moreland, L. W. et al., “Treatment ofRheumatoid Arthritis with a Recombinant Human Tumor Necrosis FactorReceptor (P75)-Fc Fusion Protein,” New England J. of Medicine, 337 (3),pp. 141-147 (1997).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The compounds of formula (I) of the invention can be administered orallyor parenterally, such as subcutaneously or intravenously, as well as bynasal application, rectally or sublingually to various mammalian speciesknown to be subject to such maladies, e.g., humans, in an effectiveamount up to 1 gram, preferably up to 200 mg, more preferably up to 100mg in a regimen of single, two or four divided daily doses.

The compounds of the formula (I) can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds can, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release can be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds canalso be administered liposomally.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I can also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which can contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid, or Cremaphor.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

It will be understood that the specific dose level and frequency ofdosage for any particular subject can be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the species, age, body weight, general health, sex and diet of thesubject, the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition.

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow.

1. A compound or a pharmaceutically acceptable salt or a stereoisomeraccording to Formula I:

wherein, R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo,CF₃, CN, OR⁵NR⁶R^(6a); R² is selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,COOR⁷ and CONR⁷R^(7a); R³ and R^(3a) are hydrogen or R³ and R^(3a) takentogether form a double bond with oxygen; R⁴ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl; R⁵ is selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, CHF₂ andCF₃; R⁶ and R^(6a) are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl and heteroarylalkyl; or R⁶ and R^(6a) taken together can formcycloalkyl or heterocyclyl; R⁷ and R^(7a) are each independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,heteroaryl, arylalkyl and heteroarylalkyl; or R⁷ and R^(7a) takentogether can form cycloalkyl or heterocyclyl; Y is selected from thegroup consisting of CO and S(O)₂; Z is selected from the groupconsisting of a direct bond, oxygen, NR⁸ and alkyl; R⁸ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, beteroaryl,arylalkyl and heteroarylalkyl; or R⁴ and R⁸ taken together can formcycloalkyl or heterocyclyl; n is an integer of 0 or
 1. 2. The compoundaccording to claim 1 wherein, Y is S(O)₂.
 3. The compound according toclaim 2 wherein, Z is a direct bond.
 4. The compound according to claim3 wherein, R¹ is selected from the group consisting of aryl andheteroaryl.
 5. The compound according to claim 4 wherein, R² is selectedfrom the group consisting of aryl and heteroaryl.
 6. The compoundaccording to claim 5 wherein, R⁴ is aryl.
 7. The compound according toclaim 6 wherein, n is
 1. 8. The compound according to claim 1 whereinthe compound is selected from the group consisting of:


9. A pharmaceutical composition, comprising a therapeutically effectiveamount of at least one compound according to claim 1; and at least onepharmaceutically acceptable diluent or carrier.